Clinical features and treatment of methylmalonic acidemia complicated with Dandy-Walker continuum: a report of 4 cases and review of literature

Clinical features and treatment of methylmalonic acidemia complicated with Dandy-Walker continuum: a report of 4 cases and review of literature | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Clinical features and treatment of methylmalonic acidemia complicated with Dandy-Walker continuum: a report of 4 cases and review of literature Weiping Wang, Yabing Zhou, Feng Jiang, Jia Wei, Jiaqi Feng, Weiwei Mao, and 1 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3988212/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Purpose The clinical characteristics and treatment of the rare methylmalonic academia (MMA) with Dandy-Walker continuum (DWC) are still unclear. The purpose of this paper is to provide novel insights into the rare pediatric disease. Methods The database of MMA cases from pediatric intensive care unit of our hospital from 2006 to 2021 was chosen, from which cases combined with DWC were selected. The characteristics of onset age, clinical manifestations, gene types, treatment and prognosis of these cases were analyzed. The diagnosis of MMA was confirmed by blood and urine tandem mass spectrometry while the diagnosis of DWC was confirmed by cranial magnetic resonance imaging (MRI). Follow-ups were performed by means of telephone inquiry or outpatient visit. Results A total of 198 children with MMA were screened, 4 of whom were complicated with DWC including 3 males and 1 female. The average age of onset was 38 days (range 4–60 days). Vomiting (3/4) was the most obvious symptom. The head circumference was small in 2 cases while normal in the rest. The blood homocysteine was 130.8-187.3 umol/L, and the urine MMA was 24.5-236.1 mmol/mol·creatinine. Blood C3 and C3/C2 levels were significantly increased in 4 children. MRI showed that the cerebellar vermis was dysplastic, and cystic dilatation of the fourth ventricle caused upward displacement of the tentorium and sinuses. All the 4 children were treated with drugs and special milk powder for the primary disease. Case 3 suffered from acute intracranial pressure (ICP) increase during hospitalization, resulting in respiratory and circulatory failure, and was treated with dehydration, lowering ICP and ventilator-assisted ventilation. However, these measures had minimum effect, and the patient died of multiple organ dysfunction syndrome 27 days after admission. In case 1, 2, and 4, ventriculoperitoneal shunt (VPS) was performed for the increased ICP. Case 1 died of respiratory failure 10 months after the operation, while case 2 died of severe pneumonia 96 months after the operation. Unlike the others, case 4 remained stable condition at the last follow-up of 32 months. Conclusions Concomitant DWC may be a clinical manifestation type of MMA, with early onset and severe conditions. The onset of increased ICP can often be seen. Head circumference can be in normal limits, and they can be manifested as hydrocephalus. VPS should be actively performed to treat hydrocephalus, relieve elevated ICP and improve the prognosis. Methylmalonic academia Dandy-Walker continuum metabolism disorders hydrocephalus ventriculoperitoneal shunt Figures Figure 1 Introduction Methylmalonic acidemia (MMA), also known as methylmalonic aciduria, is an organic acid metabolism disorder. It is an autosomal recessive genetic disease caused by the deficiency of methylmalonyl-CoA mutase (MAM) or cobalamin (Cbl) metabolism disorder, which leads to the metabolic disorder of methylmalonic acid[1]. MMA is often associated with multiple systems, in which the central nervous system is commonly affected[1,2]. Dandy-Walker continuum (DWC), also referred to as Dandy-Walker complex, corresponds to a group of disorders believed to represent a continuum spectrum of posterior fossa malformations[3].Conditions classically included under the term DWC include: classic Dandy-Walker malformation (DWM), vermian hypoplasia (VH), Blake's pouch cyst (BPC) and mega cisterna magna (MCM)[3]. The clinical features of DWC include behavioral and intellectual disorders, and hydrocephalus is also complicated in some cases[4]. DWC is often complicated with congenital heart diseases, cheilopalatognathus, neural tube defects, etc. DWC not only presents as an isolated congenital malformation, but also as a component of some malformation syndromes, such as Joubert syndrome, Golden syndrome and Meckel-Gruber syndrome[4,5]. MMA presents with diverse clinical manifestations which are related to the subtype of the disease and the severity of enzyme deficiency. Main clinical manifestations include anorexia, intellectual disability, movement disorders, ataxia, dystonia, hyperspasmia, epilepsy, hydrocephalus, lethargy[1,2]. As one of the most important clinical features, neurological symptoms may be presented as neuro-developmental delay, epilepsy, hydrocephalus and cerebral hemorrhage [1,6]. MMA may be complicated with DWC, however, few literatures have reported this particular disease type[7,8]. The relationship between MMA and DWC remains unknown. Here we analyzed and contrasted 4 cases who had MMA complicated with DWC from our database from January 2006 to December 2021. Methods The database of MMA cases from pediatric intensive care unit of our hospital from 2006 to 2021 was chosen, from which cases combined with DWC were selected. The characteristics of onset age, clinical manifestations, gene types, treatment and prognosis of these cases were analyzed. The diagnosis of MMA was confirmed by blood and urine tandem mass spectrometry while the diagnosis of DWC was confirmed by cranial magnetic resonance imaging (MRI). Follow-ups were performed by means of telephone inquiry or outpatient visit. Illustrative cases Case 1 A 43-day-old male infant was admitted with the chief complaint of vomiting. Two days after birth, the child Was treated with ventilator-assisted ventilation because of metabolic acidosis and respiratory failure. Hematuria tandem mass spectrometry suggested MMA. After he was treated with special formula milk powder and levocarnitine, his conditions improved slightly. He was referred to our hospital because he vomited again 43 days after birth. The patient was the second child, whose brother died of metabolic acidosis and respiratory failure 21 days after birth. Physical examination results on admission showed poor response, head circumference of 36.5cm, thick breath sounds in both lungs, liver of soft quality 3cm below the costal surface, spleen 2cm below the costal surface and warm extremities. Laboratory tests showed metabolic acidosis and abnormal liver function. Brain magnetic resonance imaging (MRI) showed cerebellar vermis volume reduction with hypoplasia, cerebellar vermis elevation, cerebellar hemisphere hypoplasia. According to the results of hematuria tandem mass spectrometry, the ratio of special milk powder to ordinary milk powder, vitamin B12 and other treatment plans were adjusted. The child was discharged from hospital in a stable condition. Six months after birth, ventriculoperitoneal shunt (VPS) was performed due to increased intracranial pressure (ICP). However, the patient died of respiratory failure after 10 months of follow-up. Case 2 A 85-day-old female infant was admitted with seizure for 4 weeks. Vomiting and poor response were also observed at first. No abnormality was seen in the history of mother pregnancy and birth history. The admission charge showed heart rate of 88 times/min, breath of 33 times/min, blood pressure of 98/66 mmHg and blood oxygen saturation of 98%. Other abnormalities including poor response, pale skin and mucous membrane, the head circumference of 34.2cm and bulging anterior fontanelle (1.5cm×2cm) were found. Limb muscle strength was normal but muscle tone was increased. During admission, blood biochemical index revealed erythrocyte of 2.43×1012/L and hemoglobin of 70g/L. Cranial MRI showed the cisterna magna of the cerebellum was dilated and communicated with the dilated fourth ventricle. The cerebellar vermis was reduced in volume without obvious lobulation, the cerebellar hemispheres were hypoplastic. Hematuria spectrum examination suggested MMA combined type. On the 5th day of admission, VPS was performed under general anesthesia. After symptomatic treatment with levocarnitine, vitamin B12, calcium folinate, hydroxycobalamin and MMA-specialized milk powder, the patient was discharged with stable conditions. After discharge, the patient received regular follow-ups, and physical examination showed that convulsion was relieved. While growth and intelligence were still under-developed, cranial computerized tomography (CT) showed ventricle was contracted compared with previous radiological results. The patient was followed up for 96 months before she died of severe pneumonia. Case 3 A 53-day-old male infant was admitted to our hospital due to vomiting for 1 week, accompanied by downward gaze of the eyes and increased muscle tension of the limbs. No abnormality was seen in the history of mother pregnancy and birth history. Physical examinations showed poor response, pale skin and mucous membrane, head circumference of 35.0cm, bulging anterior fontanelle (2cm×2cm), downward gazing of both eyes. Limb muscle strength was normal but muscle tone was increased. During admission, blood biochemical index showed erythrocyte of 2.5×10 12 /L and hemoglobin of 78g/L. Cranial MRI showed that the cerebellar vermis was reduced in volume without obvious lobulation, and the cerebellar hemispheres were hypoplastic. Hematuria spectrum examination suggested MMA combined type. Ultrasonography revealed increased echogenicity and loss of corticomedullary differentiation in both kidneys, which suggested the possibility of diffused disease of bilateral kidneys. During hospitalization, symptomatic treatment with erythrocyte transfusion was performed immediately, but no improvement of anemia was found. Thereafter, when hypertension, cardiac insufficiency, severe pneumonia, renal insufficiency and abnormal coagulation occurred, invasive ventilator-assisted ventilation was assumed. At the same time, L-carnitine, hydroxycobalamin, leucovorin, betaine, MMA specialized milk powder and other comprehensive treatments were conducted but showed poor curative effect. After 27 days of admission, the patient died of multiple organ dysfunction syndrome. Case 4 A 102-day-old male infant was admitted with the chief complaint of vomiting for more than 1 month. The vomiting exacerbated progressively, with poor response, shortness of breath, and cyanosis. After emergency invasive ventilator-assisted ventilation, the patient was transferred to pediatric intensive care unit for further treatment. Previous obstetric history showed that the patient’s mother had 2 pregnancies and 1 birth, and induced labor was performed on the 1st pregnancy due to generalized edema in the 4th month of gestation. Physical examination revealed poor response, pale skin and mucous membranes, the head circumstance of 39.0cm, bulging anterior fontanelle, wet rales in both lungs, the liver located 3cm below the rib with soft texture, and mottled extremities with slightly lower temperature. Biochemical examinations suggested anemia, metabolic acidosis, respiratory failure, and myocardial damage. Cranial MRI showed the cisterna magna of the cerebellum was dilated and communicated with the dilated fourth ventricle. The cerebellar vermis was reduced in volume without obvious lobulation, the cerebellar hemispheres were hypoplastic, and the supratentorial ventricles were dilated. Hematuria spectrum examination suggested MMA and further genetic testing suggested cblC type. During admission, symptomatic treatment was performed immediately, and the patient was treated with levocarnitine, hydroxycobalamin, betaine, methionine, folic acid, and MMA-specialized milk powder. After days of treatment, he was discharged from the hospital with stable conditions. Eight months after birth, the infant was presented with graver vomiting, apathy, poor response, and dilated fontanel. Cranial CT showed that hydrocephalus was worsened. Thus, the VPS was performed and a Medtronic adjustable pressure shunt (Model 42866, pressure 1.5) was placed successfully. Until the latest follow-up, the child was 36 months old with good mental state. Although the development of intelligence, language, and movement was still lagging behind, cranial MRI showed a smaller cerebral ventricle. Table 1 The clinical data and prognosis of 4 MMA complicated with DWC patients Case Gender Age of onset （d） Initial symptoms Head circumference (cm) Organ dysfunction Surgery Follow-up (mo) Prognosis Acidosis Abnormal coagulation Respiratory failure Myocardial damage Liver dysfunction Kidney damage Nervous system 1 M 4 Vomitting 36.5 + - - - + - + VPS 10 Death 2 F 45 Seizure 34.2 - - + - - - + VPS 96 Death 3 M 45 Vomitting 35.0 + + + + + + + None / Death 4 M 60 Vomitting 39.0 + - + + - + + VPS 32 Alive M:male,F: femal, VPS: ventriculoperitoneal shunt. Discussion There are only two studies reporting MMA complicated with DWC. Liu et al reported a female infant with development retardation, which developed rapidly into dyspnea and severe anemia. Blood examination showed an erythrocyte count of 1.04 × 10 12 /L and a hemoglobin level of 33g/L[7]. Cranial MRI suggested cerebellar vermis hypoplasia, enlargement of the fourth ventricle, and supratentorial hydrocephalus. Metabolic screening showed an increase of methylmalonic acid. Although the patient received therapies including acidosis correction, bicarbonate, blood transfusion, antibiotics treatment, mechanical ventilation, and heat preservation, unfortunately, the patient died of metabolic crisis on the 4th day after admission. In the second article, Liu et al included 34 patients with severe MMA, 28 of whom underwent cranial CT or MRI examinations. Results showed that 6 had hydrocephalus, and 3 were complicated with DWC [8]. Among the 3 cases, genetic testing was performed in 2 cases. It was found that c.609G > A homozygous mutation in one case, and c.649delG/c. 609 G > A heterozygous mutation in the other. Therefore, MMA complicated with DWC may be related to the mutation of c. 609 G > A. As to the clinical outcomes of the 3 patients, one patient died and one of them was discharged, but they all had poor prognosis. According to our study, MMA was also complicated with DWC and the results suggested that DWC might be a special feature of MMA, or that the clinical features in our study referred to an undefined syndrome with unclear characteristics. Anyhow, further researches were required to explore the correlation between MMA and DWC. The outcomes of MMA present with different severities from mild symptoms to even death. In the acute phase, it presents with anorexia, vomit, dyspnea, dystonia, hyperspasmia, stupor and even death, while it affects the nervous system mainly in the stable phase, which presents with intellectual disability, language development disorder and movement disorder, etc[1,9]. DWC often shows up with hydrocephalus, and the severity of the clinical manifestations of DWC is highly correlated with the development of vermis cerebelli and the size of the cyst [10]. In infancy, since the cranial fontanelles and the cranial suture haven’t closed, DWC shows the symptoms and clinical signs of intracranial hypertension, such as increased head circumference and disproportionate increase of posterior fossa and lambdoid suture compared to other cranial structure. In elder children, DWC presents with cognitive and motor retardation, especially in the walking ability and motor coordination ability [4,5]. In our study, we found that even if the imaging results suggested ventricular dilatation and even interstitial edema, and that physical examination suggested the increase of the fontanelle tension, the patient’s head circumference could be normal. These results show that compared to the classic DWC, DWC complicated with MMA will more likely show a normal head circumference. MMA includes quite different subtypes with diverse characteristics of onset time, severity and clinical manifestations. According to the urgency of morbidity, MMA can be divided into early-onset type and late-onset type [2]. The early-onset MMA occurs in the infant period with epilepsy and failure to thrive. Patients with early-onset MMA may be complicated with poor feeding, retinitis pigmentosa, and even dysfunctions of the blood system and the urinary system, which often leads to the poor prognosis. The late-onset MMA is a rather rare subtype, which often occurs after 4 years old with nervous disorders and psychiatric disturbances [11–13]. Although the late-onset MMA is easily misdiagnosed, satisfactory therapeutic outcomes can be achieved. DWC is an imaging diagnosis according to cranial MRI. It could be precisely diagnosed when imaging shows: aplasia or even absence of cerebellar vermis, rotation or lift upward of cerebellar vermis, aplasia with or without compression of cerebellar hemisphere and brainstem, connection of the enlarged fourth ventricle and the cerebellar-posterior cyst [5,14]. Together with our four patients and previous case reports, we find that MMA complicated with DWC is characterized by early age of onset (usually within 3 months after birth), and it often critically increases the risk of death in children. One of our patients aged 53 days died after 27 days of hospitalization. One patient in a previous report aged 3 months died after 4 days of hospitalization [7]. Thus, the complication directly increases the risk of death in the acute phase. Hydrocephalus is also common to the patients of MMA complicated with DWC, which is the focus of surgical treatment [15,16]. Some scholars had suggested that the formation mechanism of hydrocephalus might be related to cerebral vascular sclerosis, which further led to the decreased arterial compliance and increased arterial pressure. When the artery delivery pressure did not attenuate, ICP would increase, and hydrocephalus would occur [17]. At the same time, the high concentration of metabolic cysteine has toxic effects on vessel wall, which is the main cause of vascular endothelial damage [18]. When DWC is complicated with hydrocephalus, capsulectomy, cyst-peritoneal shunt, VPS and endoscopic third ventriculostomy could be performed with respective advantages and disadvantages [5,10,15,19,20]. As the children of MMA complicated with DWC often shows early age of onset and critical damages on blood system and respiratory system, VPS is recommended to be performed immediately to relieve hydrocephalus and high ICP. As for these patients, the absorption function of cerebrospinal fluid is not sufficient at the age of onset, which makes it hard for endoscopic third ventriculostomy to relieve the hydrocephalus rapidly. For this reason, VPS was performed to relieve the hydrocephalus and improve the prognosis in our three patients. Conclusion Concomitant DWC may be a clinical manifestation type of MMA, with early onset and severe conditions, and the two diseases might have the same pathologic basis. MMA complicated with DWC often presents with hydrocephalus and shows increased ICP. However, the head circumference of the children may be within the normal range. VPS should be actively performed to treat hydrocephalus, relieve elevated ICP and improve the prognosis. Declarations Ethics approval and consent to participate This study was approved by the Ethics Committee of Xinhua Hospital (Approval No. XHEC-D-2023-002). Consent for publication Not applicable. Availability of data and materials The datasets used during the current study are available from the corresponding author on reasonable request. Competing interests The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Funding Science and Technology Commission of Shanghai Municipality, Science and Technology Innovation Action Plan，NO.20Y21900500 Contributors Weiping Wang and Yabing Zhou conceptualized and designed the study and drafted the initial manuscript. Feng Jiang, Jia Wei and Jiaqi Feng collected data and reviewed and revised the manuscript. Xiaoqiang Wang and Weiwei Mao designed the study and reviewed and revised the manuscript. All authors approved the final manuscript as submitted and agree to be accountable for the content of the work. References Zhou, X.; Cui, Y.; Han, J. Methylmalonic acidemia: Current status and research priorities. Intractable & rare diseases research 2018 , 7 , 73-78, doi:10.5582/irdr.2018.01026. Baumgartner, M.R.; Hörster, F.; Dionisi-Vici, C.; Haliloglu, G.; Karall, D.; Chapman, K.A.; Huemer, M.; Hochuli, M.; Assoun, M.; Ballhausen, D.; et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. 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Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. Molecular genetics and metabolism 2006 , 88 , 315-321, doi:10.1016/j.ymgme.2006.04.001. Kang, L.; Liu, Y.; Shen, M.; Liu, Y.; He, R.; Song, J.; Jin, Y.; Li, M.; Zhang, Y.; Dong, H.; et al. A study on a cohort of 301 Chinese patients with isolated methylmalonic acidemia. J Inherit Metab Dis 2020 , 43 , 409-423, doi:10.1002/jimd.12183. Almási, T.; Guey, L.T.; Lukacs, C.; Csetneki, K.; Vokó, Z.; Zelei, T. Systematic literature review and meta-analysis on the epidemiology of methylmalonic acidemia (MMA) with a focus on MMA caused by methylmalonyl-CoA mutase (mut) deficiency. Orphanet J Rare Dis 2019 , 14 , 84, doi:10.1186/s13023-019-1063-z. Correa, G.G.; Amaral, L.F.; Vedolin, L.M. Neuroimaging of Dandy-Walker malformation: new concepts. Topics in magnetic resonance imaging : TMRI 2011 , 22 , 303-312, doi:10.1097/RMR.0b013e3182a2ca77. Zhang, K.; Gao, M.; Wang, G.; Shi, Y.; Li, X.; Lv, Y.; Zhang, G.; Gai, Z.; Liu, Y. Hydrocephalus in cblC type methylmalonic acidemia. Metab Brain Dis 2019 , 34 , 451-458, doi:10.1007/s11011-018-0351-y. Ma, M.; Wu, M.; Li, Y.; Wu, D.; Zhang, B. Shunt surgery for early-onset severe hydrocephalus in methylmalonic acidemia: report on two cases and review of the literature. Childs Nerv Syst 2018 , 34 , 1417-1421, doi:10.1007/s00381-018-3753-6. Greitz, D.; Greitz, T.; Hindmarsh, T. A new view on the CSF-circulation with the potential for pharmacological treatment of childhood hydrocephalus. Acta paediatrica (Oslo, Norway : 1992) 1997 , 86 , 125-132, doi:10.1111/j.1651-2227.1997.tb08850.x. Deodato, F.; Boenzi, S.; Santorelli, F.M.; Dionisi-Vici, C. Methylmalonic and propionic aciduria. American journal of medical genetics. Part C, Seminars in medical genetics 2006 , 142c , 104-112, doi:10.1002/ajmg.c.30090. Carmel, P.W.; Antunes, J.L.; Hilal, S.K.; Gold, A.P. Dandy-Walker syndrome: clinico-pathological features and re-evaluation of modes of treatment. Surgical neurology 1977 , 8 , 132-138. McClelland, S., 3rd; Ukwuoma, O.I.; Lunos, S.; Okuyemi, K.S. The natural history of Dandy-Walker syndrome in the United States: A population-based analysis. J Neurosci Rural Pract 2015 , 6 , 23-26, doi:10.4103/0976-3147.143185. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3988212","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":275479681,"identity":"3224931d-b405-49c1-b79a-3bf3d09d8b90","order_by":0,"name":"Weiping Wang","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Weiping","middleName":"","lastName":"Wang","suffix":""},{"id":275479682,"identity":"e0472f7d-8ba5-4587-a32c-4a6009c16abb","order_by":1,"name":"Yabing Zhou","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Yabing","middleName":"","lastName":"Zhou","suffix":""},{"id":275479683,"identity":"3f9dd96a-55a1-4e74-add2-d8ae163ad109","order_by":2,"name":"Feng Jiang","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Feng","middleName":"","lastName":"Jiang","suffix":""},{"id":275479684,"identity":"d4fa2eaf-4d54-4746-b691-1fcef36c7877","order_by":3,"name":"Jia Wei","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jia","middleName":"","lastName":"Wei","suffix":""},{"id":275479685,"identity":"be82bf32-c5bd-4bba-90e4-561e739d002f","order_by":4,"name":"Jiaqi Feng","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Jiaqi","middleName":"","lastName":"Feng","suffix":""},{"id":275479686,"identity":"93ad9970-1932-424c-9bb7-7474666a0de8","order_by":5,"name":"Weiwei Mao","email":"","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine","correspondingAuthor":false,"prefix":"","firstName":"Weiwei","middleName":"","lastName":"Mao","suffix":""},{"id":275479687,"identity":"e76badb3-2fb4-492c-8721-de0cccc12731","order_by":6,"name":"Xiaoqiang Wang","email":"data:image/png;base64,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","orcid":"","institution":"Xinhua Hospital Affiliated to Shanghai Jiaotong University School of Medicine","correspondingAuthor":true,"prefix":"","firstName":"Xiaoqiang","middleName":"","lastName":"Wang","suffix":""}],"badges":[],"createdAt":"2024-02-25 14:35:53","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3988212/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3988212/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":51825455,"identity":"87ec7def-87f6-46a6-a9b6-1481950254b3","added_by":"auto","created_at":"2024-02-29 16:59:52","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":307953,"visible":true,"origin":"","legend":"\u003cp\u003eCase 4: A 102-day-old male infant was admitted with the chief complaint of vomiting for more than 1 month. Preoperative sagittal T1-weighted contrast-enhanced MRI scans (A) showed that the posterior fossa cyst was hypointensity, and communicated with the expanded fourth ventricle. The cerebellar volume was small, the cerebellar vermis was elevated with dysplasia and no obvious lobulation was observed, the tentorium and transverse sinus were elevated. Preoperative axial T1-weighted contrast-enhanced MRI scans (B) showed that the lateral ventricle was dilated, and the accompanying sulci were not obvious. 12 months after the VPS, the sagittal (C) and axial (D) T1-weighted plain MRI scans showed that the posterior fossa cyst was smaller than that before the operation, and the cerebellum volume was larger than that before operation. The hydrocephalus was partly relieved and the supratentorial sulci was also visible. 18 months after the operation, the sagittal (E) and axial (F) cranial CT scans showed that the posterior fossa cyst was further reduced, and the shunt tube was visible in the frontal angle of the right lateral ventricle.\u003c/p\u003e","description":"","filename":"figure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-3988212/v1/2a05fa5a617ffbb6cc8ec480.jpg"},{"id":52138194,"identity":"6384179a-2260-4bcb-8618-0735877ec6d9","added_by":"auto","created_at":"2024-03-07 10:22:45","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":365478,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3988212/v1/7e1a3a48-9bf3-4321-80bd-781e831d74cc.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Clinical features and treatment of methylmalonic acidemia complicated with Dandy-Walker continuum: a report of 4 cases and review of literature","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMethylmalonic acidemia (MMA), also known as methylmalonic aciduria, is an organic acid metabolism disorder. It is an autosomal recessive genetic disease caused by the deficiency of methylmalonyl-CoA mutase (MAM) or cobalamin (Cbl) metabolism disorder, which leads to the metabolic disorder of methylmalonic acid[1]. MMA is often associated with multiple systems, in which the central nervous system is commonly affected[1,2].\u003c/p\u003e\n\u003cp\u003eDandy-Walker continuum (DWC), also referred to as Dandy-Walker complex, corresponds to a group of disorders believed to represent a continuum spectrum of posterior fossa malformations[3].Conditions classically included under the term DWC include: classic Dandy-Walker malformation (DWM), vermian hypoplasia (VH), Blake's pouch cyst (BPC) and mega cisterna magna (MCM)[3]. The clinical features of DWC include behavioral and intellectual disorders, and hydrocephalus is also complicated in some cases[4]. DWC is often complicated with congenital heart diseases, cheilopalatognathus, neural tube defects, etc. DWC not only presents as an isolated congenital malformation, but also as a component of some malformation syndromes, such as Joubert syndrome, Golden syndrome and Meckel-Gruber syndrome[4,5].\u003c/p\u003e\n\u003cp\u003eMMA presents with diverse clinical manifestations which are related to the subtype of the disease and the severity of enzyme deficiency. Main clinical manifestations include anorexia, intellectual disability, movement disorders, ataxia, dystonia, hyperspasmia, epilepsy, hydrocephalus, lethargy[1,2]. As one of the most important clinical features, neurological symptoms may be presented as neuro-developmental delay, epilepsy, hydrocephalus and cerebral hemorrhage [1,6]. MMA may be complicated with DWC, however, few literatures have reported this particular disease type[7,8]. The relationship between MMA and DWC remains unknown. Here we analyzed and contrasted 4 cases who had MMA complicated with DWC from our database from January 2006 to December 2021.\u003c/p\u003e"},{"header":"Methods","content":"\u003cp\u003eThe database of MMA cases from pediatric intensive care unit of our hospital from 2006 to 2021 was chosen, from which cases combined with DWC were selected. The characteristics of onset age, clinical manifestations, gene types, treatment and prognosis of these cases were analyzed. The diagnosis of MMA was confirmed by blood and urine tandem mass spectrometry while the diagnosis of DWC was confirmed by cranial magnetic resonance imaging (MRI). Follow-ups were performed by means of telephone inquiry or outpatient visit.\u003c/p\u003e"},{"header":"Illustrative cases","content":"\u003cp\u003e\u003cstrong\u003eCase 1\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 43-day-old male infant was admitted with the chief complaint of vomiting. Two days after birth, the child Was treated with ventilator-assisted ventilation because of metabolic acidosis and respiratory failure. Hematuria tandem mass spectrometry suggested MMA. After he was treated with special formula milk powder and levocarnitine, his conditions improved slightly. He was referred to our hospital because he vomited again 43 days after birth. The patient was the second child, whose brother died of metabolic acidosis and respiratory failure 21 days after birth. Physical examination results on admission showed poor response, head circumference of 36.5cm, thick breath sounds in both lungs, liver of soft quality 3cm below the costal surface, spleen 2cm below the costal surface and warm extremities. Laboratory tests showed metabolic acidosis and abnormal liver function. Brain magnetic resonance imaging (MRI) showed cerebellar vermis volume reduction with hypoplasia, cerebellar vermis elevation, cerebellar hemisphere hypoplasia. According to the results of hematuria tandem mass spectrometry, the ratio of special milk powder to ordinary milk powder, vitamin B12 and other treatment plans were adjusted. The child was discharged from hospital in a stable condition. Six months after birth, ventriculoperitoneal shunt (VPS) was performed due to increased intracranial pressure (ICP). However, the patient died of respiratory failure after 10 months of follow-up.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 2\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 85-day-old female infant was admitted with seizure for 4 weeks. Vomiting and poor response were also observed at first. No abnormality was seen in the history of mother pregnancy and birth history. The admission charge showed heart rate of 88 times/min, breath of 33 times/min, blood pressure of 98/66 mmHg and blood oxygen saturation of 98%. Other abnormalities including poor response, pale skin and mucous membrane, the head circumference of 34.2cm and bulging anterior fontanelle (1.5cm\u0026times;2cm) were found. Limb muscle strength was normal but muscle tone was increased. During admission, blood biochemical index revealed erythrocyte of 2.43\u0026times;1012/L and hemoglobin of 70g/L. Cranial MRI showed the cisterna magna of the cerebellum was dilated and communicated with the dilated fourth ventricle. The cerebellar vermis was reduced in volume without obvious lobulation, the cerebellar hemispheres were hypoplastic. Hematuria spectrum examination suggested MMA combined type. On the 5th day of admission, VPS was performed under general anesthesia. After symptomatic treatment with levocarnitine, vitamin B12, calcium folinate, hydroxycobalamin and MMA-specialized milk powder, the patient was discharged with stable conditions. After discharge, the patient received regular follow-ups, and physical examination showed that convulsion was relieved. While growth and intelligence were still under-developed, cranial computerized tomography (CT) showed ventricle was contracted compared with previous radiological results. The patient was followed up for 96 months before she died of severe pneumonia.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 3\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 53-day-old male infant was admitted to our hospital due to vomiting for 1 week, accompanied by downward gaze of the eyes and increased muscle tension of the limbs. No abnormality was seen in the history of mother pregnancy and birth history. Physical examinations showed poor response, pale skin and mucous membrane, head circumference of 35.0cm, bulging anterior fontanelle (2cm\u0026times;2cm), downward gazing of both eyes. Limb muscle strength was normal but muscle tone was increased. During admission, blood biochemical index showed erythrocyte of 2.5\u0026times;10\u003csup\u003e12\u003c/sup\u003e/L and hemoglobin of 78g/L. Cranial MRI showed that the cerebellar vermis was reduced in volume without obvious lobulation, and the cerebellar hemispheres were hypoplastic. Hematuria spectrum examination suggested MMA combined type. Ultrasonography revealed increased echogenicity and loss of corticomedullary differentiation in both kidneys, which suggested the possibility of diffused disease of bilateral kidneys. During hospitalization, symptomatic treatment with erythrocyte transfusion was performed immediately, but no improvement of anemia was found. Thereafter, when hypertension, cardiac insufficiency, severe pneumonia, renal insufficiency and abnormal coagulation occurred, invasive ventilator-assisted ventilation was assumed. At the same time, L-carnitine, hydroxycobalamin, leucovorin, betaine, MMA specialized milk powder and other comprehensive treatments were conducted but showed poor curative effect. After 27 days of admission, the patient died of multiple organ dysfunction syndrome.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCase 4\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA 102-day-old male infant was admitted with the chief complaint of vomiting for more than 1 month. The vomiting exacerbated progressively, with poor response, shortness of breath, and cyanosis. After emergency invasive ventilator-assisted ventilation, the patient was transferred to pediatric intensive care unit for further treatment. Previous obstetric history showed that the patient\u0026rsquo;s mother had 2 pregnancies and 1 birth, and induced labor was performed on the 1st pregnancy due to generalized edema in the 4th month of gestation. Physical examination revealed poor response, pale skin and mucous membranes, the head circumstance of 39.0cm, bulging anterior fontanelle, wet rales in both lungs, the liver located 3cm below the rib with soft texture, and mottled extremities with slightly lower temperature. Biochemical examinations suggested anemia, metabolic acidosis, respiratory failure, and myocardial damage. Cranial MRI showed the cisterna magna of the cerebellum was dilated and communicated with the dilated fourth ventricle. The cerebellar vermis was reduced in volume without obvious lobulation, the cerebellar hemispheres were hypoplastic, and the supratentorial ventricles were dilated. Hematuria spectrum examination suggested MMA and further genetic testing suggested cblC type. During admission, symptomatic treatment was performed immediately, and the patient was treated with levocarnitine, hydroxycobalamin, betaine, methionine, folic acid, and MMA-specialized milk powder. After days of treatment, he was discharged from the hospital with stable conditions. Eight months after birth, the infant was presented with graver vomiting, apathy, poor response, and dilated fontanel. Cranial CT showed that hydrocephalus was worsened. Thus, the VPS was performed and a Medtronic adjustable pressure shunt (Model 42866, pressure 1.5) was placed successfully. Until the latest follow-up, the child was 36 months old with good mental state. Although the development of intelligence, language, and movement was still lagging behind, cranial MRI showed a smaller cerebral ventricle.\u003c/p\u003e\n\u003cp\u003e\u003cem\u003eTable 1\u003c/em\u003e The clinical data and prognosis of 4 MMA complicated with DWC patients\u003c/p\u003e\n\u003ctable border=\"1\" cellspacing=\"0\" cellpadding=\"0\"\u003e\n\u003ctbody\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"3\" width=\"4.16210295728368%\"\u003e\n\u003cp\u003eCase\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"5.147864184008762%\"\u003e\n\u003cp\u003eGender\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"6.790799561883899%\"\u003e\n\u003cp\u003eAge of onset\u0026nbsp;（d）\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"6.681270536692224%\"\u003e\n\u003cp\u003eInitial symptoms\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"9.309967141292443%\"\u003e\n\u003cp\u003eHead circumference (cm)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd colspan=\"7\" width=\"47.86418400876232%\"\u003e\n\u003cp\u003eOrgan dysfunction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"6.24315443592552%\"\u003e\n\u003cp\u003eSurgery\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"6.24315443592552%\"\u003e\n\u003cp\u003eFollow-up (mo)\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"3\" width=\"7.5575027382256295%\"\u003e\n\u003cp\u003ePrognosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\" height=\"13\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd rowspan=\"2\" width=\"13.043478260869565%\"\u003e\n\u003cp\u003eAcidosis\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"15.102974828375286%\"\u003e\n\u003cp\u003eAbnormal coagulation\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"15.102974828375286%\"\u003e\n\u003cp\u003eRespiratory failure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"17.391304347826086%\"\u003e\n\u003cp\u003eMyocardial damage\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"15.102974828375286%\"\u003e\n\u003cp\u003eLiver dysfunction\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"11.212814645308924%\"\u003e\n\u003cp\u003eKidney damage\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd rowspan=\"2\" width=\"13.043478260869565%\"\u003e\n\u003cp\u003eNervous system\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\" height=\"42\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"NaN%\" height=\"42\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"4.16210295728368%\"\u003e\n\u003cp\u003e1\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5.147864184008762%\"\u003e\n\u003cp\u003eM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.790799561883899%\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.681270536692224%\"\u003e\n\u003cp\u003eVomitting\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"9.309967141292443%\"\u003e\n\u003cp\u003e36.5\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8.32420591456736%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5.3669222343921135%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003eVPS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e10\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.5575027382256295%\"\u003e\n\u003cp\u003eDeath\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\" height=\"54\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"4.16210295728368%\"\u003e\n\u003cp\u003e2\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5.147864184008762%\"\u003e\n\u003cp\u003eF\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.790799561883899%\"\u003e\n\u003cp\u003e45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.681270536692224%\"\u003e\n\u003cp\u003e\u0026nbsp;Seizure\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"9.309967141292443%\"\u003e\n\u003cp\u003e34.2\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8.32420591456736%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5.3669222343921135%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003eVPS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e96\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.5575027382256295%\"\u003e\n\u003cp\u003eDeath\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\" height=\"54\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"4.16210295728368%\"\u003e\n\u003cp\u003e3\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5.147864184008762%\"\u003e\n\u003cp\u003eM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.790799561883899%\"\u003e\n\u003cp\u003e45\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.681270536692224%\"\u003e\n\u003cp\u003eVomitting\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"9.309967141292443%\"\u003e\n\u003cp\u003e35.0\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8.32420591456736%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5.3669222343921135%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003eNone\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e/\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.5575027382256295%\"\u003e\n\u003cp\u003eDeath\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\" height=\"54\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003ctr\u003e\n\u003ctd width=\"4.16210295728368%\"\u003e\n\u003cp\u003e4\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5.147864184008762%\"\u003e\n\u003cp\u003eM\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.790799561883899%\"\u003e\n\u003cp\u003e60\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.681270536692224%\"\u003e\n\u003cp\u003eVomitting\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"9.309967141292443%\"\u003e\n\u003cp\u003e39.0\u0026nbsp;\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"8.32420591456736%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.228915662650603%\"\u003e\n\u003cp\u003e-\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"5.3669222343921135%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e+\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003eVPS\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"6.24315443592552%\"\u003e\n\u003cp\u003e32\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"7.5575027382256295%\"\u003e\n\u003cp\u003eAlive\u003c/p\u003e\n\u003c/td\u003e\n\u003ctd width=\"0%\" height=\"54\"\u003e\u0026nbsp;\u003c/td\u003e\n\u003c/tr\u003e\n\u003c/tbody\u003e\n\u003c/table\u003e\n\u003cp\u003eM:male,F: femal, VPS: ventriculoperitoneal shunt.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThere are only two studies reporting MMA complicated with DWC. \u003cem\u003eLiu et al\u003c/em\u003e reported a female infant with development retardation, which developed rapidly into dyspnea and severe anemia. Blood examination showed an erythrocyte count of 1.04 \u0026times; 10\u003csup\u003e12\u003c/sup\u003e/L and a hemoglobin level of 33g/L[7]. Cranial MRI suggested cerebellar vermis hypoplasia, enlargement of the fourth ventricle, and supratentorial hydrocephalus. Metabolic screening showed an increase of methylmalonic acid. Although the patient received therapies including acidosis correction, bicarbonate, blood transfusion, antibiotics treatment, mechanical ventilation, and heat preservation, unfortunately, the patient died of metabolic crisis on the 4th day after admission. In the second article, \u003cem\u003eLiu et al\u003c/em\u003e included 34 patients with severe MMA, 28 of whom underwent cranial CT or MRI examinations. Results showed that 6 had hydrocephalus, and 3 were complicated with DWC [8]. Among the 3 cases, genetic testing was performed in 2 cases. It was found that c.609G\u0026thinsp;\u0026gt;\u0026thinsp;A homozygous mutation in one case, and c.649delG/c. 609 G\u0026thinsp;\u0026gt;\u0026thinsp;A heterozygous mutation in the other. Therefore, MMA complicated with DWC may be related to the mutation of c. 609 G\u0026thinsp;\u0026gt;\u0026thinsp;A. As to the clinical outcomes of the 3 patients, one patient died and one of them was discharged, but they all had poor prognosis. According to our study, MMA was also complicated with DWC and the results suggested that DWC might be a special feature of MMA, or that the clinical features in our study referred to an undefined syndrome with unclear characteristics. Anyhow, further researches were required to explore the correlation between MMA and DWC.\u003c/p\u003e \u003cp\u003eThe outcomes of MMA present with different severities from mild symptoms to even death. In the acute phase, it presents with anorexia, vomit, dyspnea, dystonia, hyperspasmia, stupor and even death, while it affects the nervous system mainly in the stable phase, which presents with intellectual disability, language development disorder and movement disorder, etc[1,9]. DWC often shows up with hydrocephalus, and the severity of the clinical manifestations of DWC is highly correlated with the development of vermis cerebelli and the size of the cyst [10]. In infancy, since the cranial fontanelles and the cranial suture haven\u0026rsquo;t closed, DWC shows the symptoms and clinical signs of intracranial hypertension, such as increased head circumference and disproportionate increase of posterior fossa and lambdoid suture compared to other cranial structure. In elder children, DWC presents with cognitive and motor retardation, especially in the walking ability and motor coordination ability [4,5]. In our study, we found that even if the imaging results suggested ventricular dilatation and even interstitial edema, and that physical examination suggested the increase of the fontanelle tension, the patient\u0026rsquo;s head circumference could be normal. These results show that compared to the classic DWC, DWC complicated with MMA will more likely show a normal head circumference.\u003c/p\u003e \u003cp\u003eMMA includes quite different subtypes with diverse characteristics of onset time, severity and clinical manifestations. According to the urgency of morbidity, MMA can be divided into early-onset type and late-onset type [2]. The early-onset MMA occurs in the infant period with epilepsy and failure to thrive. Patients with early-onset MMA may be complicated with poor feeding, retinitis pigmentosa, and even dysfunctions of the blood system and the urinary system, which often leads to the poor prognosis. The late-onset MMA is a rather rare subtype, which often occurs after 4 years old with nervous disorders and psychiatric disturbances [11\u0026ndash;13]. Although the late-onset MMA is easily misdiagnosed, satisfactory therapeutic outcomes can be achieved. DWC is an imaging diagnosis according to cranial MRI. It could be precisely diagnosed when imaging shows: aplasia or even absence of cerebellar vermis, rotation or lift upward of cerebellar vermis, aplasia with or without compression of cerebellar hemisphere and brainstem, connection of the enlarged fourth ventricle and the cerebellar-posterior cyst [5,14]. Together with our four patients and previous case reports, we find that MMA complicated with DWC is characterized by early age of onset (usually within 3 months after birth), and it often critically increases the risk of death in children. One of our patients aged 53 days died after 27 days of hospitalization. One patient in a previous report aged 3 months died after 4 days of hospitalization [7]. Thus, the complication directly increases the risk of death in the acute phase.\u003c/p\u003e \u003cp\u003eHydrocephalus is also common to the patients of MMA complicated with DWC, which is the focus of surgical treatment [15,16]. Some scholars had suggested that the formation mechanism of hydrocephalus might be related to cerebral vascular sclerosis, which further led to the decreased arterial compliance and increased arterial pressure. When the artery delivery pressure did not attenuate, ICP would increase, and hydrocephalus would occur [17]. At the same time, the high concentration of metabolic cysteine has toxic effects on vessel wall, which is the main cause of vascular endothelial damage [18]. When DWC is complicated with hydrocephalus, capsulectomy, cyst-peritoneal shunt, VPS and endoscopic third ventriculostomy could be performed with respective advantages and disadvantages [5,10,15,19,20]. As the children of MMA complicated with DWC often shows early age of onset and critical damages on blood system and respiratory system, VPS is recommended to be performed immediately to relieve hydrocephalus and high ICP. As for these patients, the absorption function of cerebrospinal fluid is not sufficient at the age of onset, which makes it hard for endoscopic third ventriculostomy to relieve the hydrocephalus rapidly. For this reason, VPS was performed to relieve the hydrocephalus and improve the prognosis in our three patients.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eConcomitant DWC may be a clinical manifestation type of MMA, with early onset and severe conditions, and the two diseases might have the same pathologic basis. MMA complicated with DWC often presents with hydrocephalus and shows increased ICP. However, the head circumference of the children may be within the normal range. VPS should be actively performed to treat hydrocephalus, relieve elevated ICP and improve the prognosis.\u003c/p\u003e"},{"header":"Declarations","content":"\u003ch2\u003eEthics approval and consent to participate\u003c/h2\u003e\n\u003cp\u003eThis study was approved by the Ethics Committee of Xinhua Hospital (Approval No. XHEC-D-2023-002).\u003c/p\u003e\n\u003ch2\u003eConsent for publication\u003c/h2\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003ch2\u003eAvailability of data and materials\u003c/h2\u003e\n\u003cp\u003eThe datasets used during the current study are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003ch2\u003eCompeting interests\u003c/h2\u003e\n\u003cp\u003eThe authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.\u003c/p\u003e\n\u003ch2\u003eFunding\u003c/h2\u003e\n\u003cp\u003eScience and Technology Commission of Shanghai Municipality, Science and Technology Innovation Action Plan，NO.20Y21900500\u003c/p\u003e\n\u003ch2\u003eContributors\u003c/h2\u003e\n\u003cp\u003eWeiping Wang and Yabing Zhou conceptualized and designed the study and drafted the initial manuscript.\u003c/p\u003e\n\u003cp\u003eFeng Jiang, Jia Wei and Jiaqi Feng collected data and reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eXiaoqiang Wang and Weiwei Mao designed the study and reviewed and revised the manuscript.\u003c/p\u003e\n\u003cp\u003eAll authors approved the final manuscript as submitted and agree to be accountable for the content of the work.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eZhou, X.; Cui, Y.; Han, J. Methylmalonic acidemia: Current status and research priorities. \u003cem\u003eIntractable \u0026amp; rare diseases research \u003c/em\u003e\u003cstrong\u003e2018\u003c/strong\u003e, \u003cem\u003e7\u003c/em\u003e, 73-78, doi:10.5582/irdr.2018.01026.\u003c/li\u003e\n\u003cli\u003eBaumgartner, M.R.; H\u0026ouml;rster, F.; Dionisi-Vici, C.; Haliloglu, G.; Karall, D.; Chapman, K.A.; Huemer, M.; Hochuli, M.; Assoun, M.; Ballhausen, D.; et al. Proposed guidelines for the diagnosis and management of methylmalonic and propionic acidemia. \u003cem\u003eOrphanet J Rare Dis \u003c/em\u003e\u003cstrong\u003e2014\u003c/strong\u003e, \u003cem\u003e9\u003c/em\u003e, 130, doi:10.1186/s13023-014-0130-8.\u003c/li\u003e\n\u003cli\u003eMoore, Kevin R. Diagnostic Imaging. Pediatric Neuroradiology. Third edition. Philadelphia: Elsevier; 2020.\u003c/li\u003e\n\u003cli\u003eZamora, E.A.; Ahmad, T. Dandy Walker Malformation. In \u003cem\u003eStatPearls\u003c/em\u003e; StatPearls Publishing Copyright \u0026copy; 2022, StatPearls Publishing LLC.: Treasure Island (FL), 2022.\u003c/li\u003e\n\u003cli\u003eSpennato, P.; Mirone, G.; Nastro, A.; Buonocore, M.C.; Ruggiero, C.; Trischitta, V.; Aliberti, F.; Cinalli, G. Hydrocephalus in Dandy-Walker malformation. \u003cem\u003eChilds Nerv Syst \u003c/em\u003e\u003cstrong\u003e2011\u003c/strong\u003e, \u003cem\u003e27\u003c/em\u003e, 1665-1681, doi:10.1007/s00381-011-1544-4.\u003c/li\u003e\n\u003cli\u003eHuemer, M.; Diodato, D.; Schwahn, B.; Schiff, M.; Bandeira, A.; Benoist, J.F.; Burlina, A.; Cerone, R.; Couce, M.L.; Garcia-Cazorla, A.; et al. Guidelines for diagnosis and management of the cobalamin-related remethylation disorders cblC, cblD, cblE, cblF, cblG, cblJ and MTHFR deficiency. \u003cem\u003eJ Inherit Metab Dis \u003c/em\u003e\u003cstrong\u003e2017\u003c/strong\u003e, \u003cem\u003e40\u003c/em\u003e, 21-48, doi:10.1007/s10545-016-9991-4.\u003c/li\u003e\n\u003cli\u003eLiu, J.; Liu, Z.; Yan, H.; Li, Y. Dandy-Walker malformation in methylmalonic acidemia: a rare case report. \u003cem\u003eBMC Pediatr \u003c/em\u003e\u003cstrong\u003e2021\u003c/strong\u003e, \u003cem\u003e21\u003c/em\u003e, 398, doi:10.1186/s12887-021-02874-y.\u003c/li\u003e\n\u003cli\u003eLiu M, C.L., Wang Q. Clinical characteristics and gene analysis of critical methylmalonic acidemia in children.\u003cem\u003e J Clin Pediatr \u003c/em\u003e\u003cstrong\u003e2019\u003c/strong\u003e, \u003cem\u003e37\u003c/em\u003e, 885-888.\u003c/li\u003e\n\u003cli\u003eHe, R.; Zhang, H.; Kang, L.; Li, H.; Shen, M.; Zhang, Y.; Mo, R.; Liu, Y.; Song, J.; Chen, Z.; et al. Analysis of 70 patients with hydrocephalus due to cobalamin C deficiency. \u003cem\u003eNeurology \u003c/em\u003e\u003cstrong\u003e2020\u003c/strong\u003e, \u003cem\u003e95\u003c/em\u003e, e3129-e3137, doi:10.1212/WNL.0000000000010912.\u003c/li\u003e\n\u003cli\u003eYengo-Kahn, A.M.; Wellons, J.C.; Hankinson, T.C.; Hauptman, J.S.; Jackson, E.M.; Jensen, H.; Krieger, M.D.; Kulkarni, A.V.; Limbrick, D.D.; McDonald, P.J.; et al. Treatment strategies for hydrocephalus related to Dandy-Walker syndrome: evaluating procedure selection and success within the Hydrocephalus Clinical Research Network. \u003cem\u003eJournal of Neurosurgery: Pediatrics \u003c/em\u003e\u003cstrong\u003e2021\u003c/strong\u003e, \u003cem\u003e28\u003c/em\u003e, 93-101, doi:10.3171/2020.11.Peds20806.\u003c/li\u003e\n\u003cli\u003eMorel, C.F.; Lerner-Ellis, J.P.; Rosenblatt, D.S. Combined methylmalonic aciduria and homocystinuria (cblC): phenotype-genotype correlations and ethnic-specific observations. \u003cem\u003eMolecular genetics and metabolism \u003c/em\u003e\u003cstrong\u003e2006\u003c/strong\u003e, \u003cem\u003e88\u003c/em\u003e, 315-321, doi:10.1016/j.ymgme.2006.04.001.\u003c/li\u003e\n\u003cli\u003eKang, L.; Liu, Y.; Shen, M.; Liu, Y.; He, R.; Song, J.; Jin, Y.; Li, M.; Zhang, Y.; Dong, H.; et al. A study on a cohort of 301 Chinese patients with isolated methylmalonic acidemia. \u003cem\u003eJ Inherit Metab Dis \u003c/em\u003e\u003cstrong\u003e2020\u003c/strong\u003e, \u003cem\u003e43\u003c/em\u003e, 409-423, doi:10.1002/jimd.12183.\u003c/li\u003e\n\u003cli\u003eAlm\u0026aacute;si, T.; Guey, L.T.; Lukacs, C.; Csetneki, K.; Vok\u0026oacute;, Z.; Zelei, T. Systematic literature review and meta-analysis on the epidemiology of methylmalonic acidemia (MMA) with a focus on MMA caused by methylmalonyl-CoA mutase (mut) deficiency. \u003cem\u003eOrphanet J Rare Dis \u003c/em\u003e\u003cstrong\u003e2019\u003c/strong\u003e, \u003cem\u003e14\u003c/em\u003e, 84, doi:10.1186/s13023-019-1063-z.\u003c/li\u003e\n\u003cli\u003eCorrea, G.G.; Amaral, L.F.; Vedolin, L.M. Neuroimaging of Dandy-Walker malformation: new concepts. \u003cem\u003eTopics in magnetic resonance imaging : TMRI \u003c/em\u003e\u003cstrong\u003e2011\u003c/strong\u003e, \u003cem\u003e22\u003c/em\u003e, 303-312, doi:10.1097/RMR.0b013e3182a2ca77.\u003c/li\u003e\n\u003cli\u003eZhang, K.; Gao, M.; Wang, G.; Shi, Y.; Li, X.; Lv, Y.; Zhang, G.; Gai, Z.; Liu, Y. Hydrocephalus in cblC type methylmalonic acidemia. \u003cem\u003eMetab Brain Dis \u003c/em\u003e\u003cstrong\u003e2019\u003c/strong\u003e, \u003cem\u003e34\u003c/em\u003e, 451-458, doi:10.1007/s11011-018-0351-y.\u003c/li\u003e\n\u003cli\u003eMa, M.; Wu, M.; Li, Y.; Wu, D.; Zhang, B. Shunt surgery for early-onset severe hydrocephalus in methylmalonic acidemia: report on two cases and review of the literature. \u003cem\u003eChilds Nerv Syst \u003c/em\u003e\u003cstrong\u003e2018\u003c/strong\u003e, \u003cem\u003e34\u003c/em\u003e, 1417-1421, doi:10.1007/s00381-018-3753-6.\u003c/li\u003e\n\u003cli\u003eGreitz, D.; Greitz, T.; Hindmarsh, T. A new view on the CSF-circulation with the potential for pharmacological treatment of childhood hydrocephalus. \u003cem\u003eActa paediatrica (Oslo, Norway : 1992) \u003c/em\u003e\u003cstrong\u003e1997\u003c/strong\u003e, \u003cem\u003e86\u003c/em\u003e, 125-132, doi:10.1111/j.1651-2227.1997.tb08850.x.\u003c/li\u003e\n\u003cli\u003eDeodato, F.; Boenzi, S.; Santorelli, F.M.; Dionisi-Vici, C. Methylmalonic and propionic aciduria. \u003cem\u003eAmerican journal of medical genetics. Part C, Seminars in medical genetics \u003c/em\u003e\u003cstrong\u003e2006\u003c/strong\u003e, \u003cem\u003e142c\u003c/em\u003e, 104-112, doi:10.1002/ajmg.c.30090.\u003c/li\u003e\n\u003cli\u003eCarmel, P.W.; Antunes, J.L.; Hilal, S.K.; Gold, A.P. Dandy-Walker syndrome: clinico-pathological features and re-evaluation of modes of treatment. \u003cem\u003eSurgical neurology \u003c/em\u003e\u003cstrong\u003e1977\u003c/strong\u003e, \u003cem\u003e8\u003c/em\u003e, 132-138.\u003c/li\u003e\n\u003cli\u003eMcClelland, S., 3rd; Ukwuoma, O.I.; Lunos, S.; Okuyemi, K.S. The natural history of Dandy-Walker syndrome in the United States: A population-based analysis. \u003cem\u003eJ Neurosci Rural Pract \u003c/em\u003e\u003cstrong\u003e2015\u003c/strong\u003e, \u003cem\u003e6\u003c/em\u003e, 23-26, doi:10.4103/0976-3147.143185.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Methylmalonic academia, Dandy-Walker continuum, metabolism disorders, hydrocephalus, ventriculoperitoneal shunt","lastPublishedDoi":"10.21203/rs.3.rs-3988212/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3988212/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003ePurpose\u003c/h2\u003e \u003cp\u003eThe clinical characteristics and treatment of the rare methylmalonic academia (MMA) with Dandy-Walker continuum (DWC) are still unclear. The purpose of this paper is to provide novel insights into the rare pediatric disease.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe database of MMA cases from pediatric intensive care unit of our hospital from 2006 to 2021 was chosen, from which cases combined with DWC were selected. The characteristics of onset age, clinical manifestations, gene types, treatment and prognosis of these cases were analyzed. The diagnosis of MMA was confirmed by blood and urine tandem mass spectrometry while the diagnosis of DWC was confirmed by cranial magnetic resonance imaging (MRI). Follow-ups were performed by means of telephone inquiry or outpatient visit.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eA total of 198 children with MMA were screened, 4 of whom were complicated with DWC including 3 males and 1 female. The average age of onset was 38 days (range 4\u0026ndash;60 days). Vomiting (3/4) was the most obvious symptom. The head circumference was small in 2 cases while normal in the rest. The blood homocysteine was 130.8-187.3 umol/L, and the urine MMA was 24.5-236.1 mmol/mol\u0026middot;creatinine. Blood C3 and C3/C2 levels were significantly increased in 4 children. MRI showed that the cerebellar vermis was dysplastic, and cystic dilatation of the fourth ventricle caused upward displacement of the tentorium and sinuses. All the 4 children were treated with drugs and special milk powder for the primary disease. Case 3 suffered from acute intracranial pressure (ICP) increase during hospitalization, resulting in respiratory and circulatory failure, and was treated with dehydration, lowering ICP and ventilator-assisted ventilation. However, these measures had minimum effect, and the patient died of multiple organ dysfunction syndrome 27 days after admission. In case 1, 2, and 4, ventriculoperitoneal shunt (VPS) was performed for the increased ICP. Case 1 died of respiratory failure 10 months after the operation, while case 2 died of severe pneumonia 96 months after the operation. Unlike the others, case 4 remained stable condition at the last follow-up of 32 months.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eConcomitant DWC may be a clinical manifestation type of MMA, with early onset and severe conditions. The onset of increased ICP can often be seen. Head circumference can be in normal limits, and they can be manifested as hydrocephalus. VPS should be actively performed to treat hydrocephalus, relieve elevated ICP and improve the prognosis.\u003c/p\u003e","manuscriptTitle":"Clinical features and treatment of methylmalonic acidemia complicated with Dandy-Walker continuum: a report of 4 cases and review of literature","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-02-29 16:59:47","doi":"10.21203/rs.3.rs-3988212/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6a92cc09-e1e9-46f5-8455-5c2381ce23d7","owner":[],"postedDate":"February 29th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-07T10:22:01+00:00","versionOfRecord":[],"versionCreatedAt":"2024-02-29 16:59:47","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3988212","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3988212","identity":"rs-3988212","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}